Organic chemist Song Lin draws on techniques from electrochemistry to overcome long-standing challenges in his own field.
Elizabeth Nelson; Lindsay France (UPhoto)
Elizabeth Nelson; Lindsay France (UPhoto)

Electric-Powered Organic Chemistry

by J. Edward Anthony

Song Lin, Chemistry and Chemical Biology, starts with simple chemical components that are widely available. From those basic ingredients, he finds ways to generate complex organic molecules for use in medicine and industry. “It’s almost like playing with Legos,” Lin says. “You have to build a complex structure starting from simple materials. It’s a strategy game.”

As part of his strategy, in 2016 Lin began experimenting with electrochemistry. “With chemistry, you usually think of mixing reagents in a flask and then heating it up to drive the reaction,” says Lin. “Electrochemistry is different. Instead of using heat, you plug electrodes in a flask and use electricity to power the reaction. Organic chemists have been using electrochemistry for a long time, but it really hasn’t entered into the mainstream for organic synthesis.”

An Old Problem for a New Solution

When Lin took up electrochemistry, he was looking for more efficient and cost-effective ways of producing medically relevant molecules. He hadn’t intended to tackle one of the more enduring and stubborn problems in organic synthesis: asymmetric hydrocyanation of alkenes.

One of Lin’s electrochemical experiments involved copper-promoted cyanation, a reaction that binds a cyanide group to a molecular substrate. To catalyze the reaction, copper has to be oxidized via an oxidation-reduction reaction. Oxidation is a notoriously misleading term (oxygen isn’t necessarily involved), and the actual behavior of subatomic particles is complex—but in simple terms, this means that copper must lose an electron in order to play its part in the reaction. To get there, an organic chemist typically would have to find an additional chemical reagent, something that can oxidize the copper catalyst without interfering with the rest of the reaction. Lin’s lab was using electricity instead. “Electrochemistry is the cleanest, most direct way of doing oxidation-reduction reactions,” says Lin, “because electrochemistry is all about electron transfer.”

While students in his lab were working on the experiment, Lin went out of town for a conference, where he happened to hear someone talking about a related but different reaction, in which cobalt catalyzes a hydrogen atom transfer.

“I heard about the cobalt-induced hydrogen atom transfer,” says Lin, “and I thought, ‘Why can’t we introduce that into our electrochemical cyanation reaction?’”

Why do that? Because, roughly speaking, a hydrogen atom transfer plus cyanation equals hydrocyanation. Historically, it’s been a huge challenge. A positively charged hydrogen ion and a negatively charged cyanide ion bond to a molecular substrate. “The two sides of the reaction have to occur simultaneously in the same system, because the intermediaries are too unstable,” Lin explains.

In the early 1990s, scientists at Dupont devised a relatively efficient and inexpensive method for hydrocyanation. Their reaction produced naproxen, a component of naproxen sodium—better known as Aleve. Naproxen sodium was already a popular over-the-counter painkiller at the time, and finding a cheaper means of producing it was a valuable discovery.

The chemists at Dupont simplified hydrocyanation by identifying a single catalyst to drive both sides of the reaction. But further experimentation found that their one-stone-for-two-birds method worked with only one type of alkene substrate. It could make only naproxen. To develop drug analogs—compounds similar to naproxen that might have different therapeutic benefits—organic chemists would have to find a means of hydrocyanation that works with other substrates.

Electricity Generates Simplicity

Lin knew that copper and cobalt, to be activated as catalysts for the two sides of the hydrocyanation reaction, would need exactly the same thing: a single electron oxidation.

Lin didn’t wait to get home. The idea was so simple that he sent it in a text message to a postdoctoral fellow in his lab. An electric current, Lin believed, would activate both catalysts, eliminating the need for additional reagents and all the messy compatibility issues that would ensue. A few days later, Lin received an understated response: “For initial results—we got some pretty good results, actually.”

“You have to know the important problems and constantly be thinking about how to use what you know. The ideas don’t come from nowhere. They come from knowledge.”

Since then, Lin’s lab has refined the technique. “Now, instead of needing to optimize a single catalyst that has to be really good at doing two different things—both the hydrogen atom transfer and the cyanation for any particular substrate—we can optimize two catalysts independently,” Lin says. With two distinct catalysts to drive the two sides of the reaction, Lin’s hydrocyanation reaction has the flexibility to work with a wide range of substrates.

For Lin, the story illustrates the importance of having broad knowledge of your field and always keeping big challenges in mind. “If we had just combined two random processes, and it worked but didn’t generate anything interesting, then it wouldn’t have been a good idea,” says Lin. “You have to know the important problems and constantly be thinking about how to use what you know. The ideas don’t come from nowhere. They come from knowledge.”

The Ingredients for Innovation

“What really excites me is coming up with new concepts and new ideas,” says Lin, “especially interdisciplinary ideas, where you use a technique that’s been studied for other purposes, like making batteries, but that’s foreign to organic chemistry. And you have to figure out how to marry these two different ideas.”

Electrochemistry is just one of the ways that Lin is rethinking methods that organic chemists have relied on for decades. His lab is beginning to explore photochemistry, which uses light to drive aspects of a chemical reaction, in combination with electrochemistry and other methods.

Lin extols the importance of understanding how and why a reaction works. “How do the bonds break and how do the bonds form, and how did the electrons transfer during this process? That is very hard to analyze, but it’s always fascinated me,” he says. Automated, high-throughput instruments that run dozens of reactions at a time have enabled a lot of findings, but Lin believes genuine breakthroughs depend on understanding the underlying mechanisms: “In my lab, we use trial-and-error processes, of course. But we also study the reaction mechanisms in depth. We try to understand what’s going on—how does it work, or why doesn’t it work, and how can we prove it? Then we take feedback from trial and error and design new reactions.”

“It’s good training for graduate students,” Lin adds. “They really analyze the reaction results and the data, and then we think methodically about experimental design and solving problems. I want to help my students realize their career dreams. Cultivating problem-solving and troubleshooting skills is critical toward making those dreams a reality.”

Lin became fascinated with synthesizing large molecules and understanding how the transformations happen as an undergraduate in China. “It’s my passion. In graduate school, I almost switched to a different research area just because it was the hot topic at the time. I’m really happy and lucky I didn’t.”